Nivolumab + Trametinib (+/- Ipilimumab) for Colorectal Cancer

(CheckMate 9N9 Trial)

Recruiting at 99 trial locations

Overseen By Mohd Khushman, Site 0022

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Bristol-Myers Squibb

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: BRAF V600, Brain metastases, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

325 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a combination of drugs to treat patients with advanced colon or rectal cancer who have already tried other treatments. The drugs help the immune system fight cancer and block proteins that help cancer grow. One of the drugs being tested has shown promise in treating advanced colorectal cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on certain treatments like corticosteroids or other immunosuppressive drugs within 14 days before starting the study.

What data supports the effectiveness of the drug combination Nivolumab, Trametinib, and Ipilimumab for colorectal cancer?

Research shows that Nivolumab, especially when combined with Ipilimumab, is effective for treating a specific type of colorectal cancer called microsatellite instability-high (MSI-H) metastatic colorectal cancer. This combination has been approved by the FDA for patients whose cancer has progressed after other treatments. ^{1 2 3 4 5}

What safety information is available for the combination of Nivolumab, Trametinib, and Ipilimumab?

The combination of nivolumab and ipilimumab has been associated with increased risk of immune-related side effects, such as colitis (inflammation of the colon), pneumonitis (lung inflammation), and diarrhea. These side effects are more common when the drugs are used together compared to nivolumab alone. The safety profile of these drugs in combination reflects the side effects of each drug individually. ^{6 7 8 9 10}

What makes the drug combination of Nivolumab, Trametinib, and possibly Ipilimumab unique for colorectal cancer?

This drug combination is unique because it targets colorectal cancer with high microsatellite instability (MSI-H) by using Nivolumab, a PD-1 inhibitor, which helps the immune system attack cancer cells, and Trametinib, which targets specific cancer cell growth pathways. The addition of Ipilimumab, which further stimulates the immune response, may enhance the effectiveness of the treatment. ^{1 2 3 4 11}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for individuals with Stage IV colorectal cancer that has spread and was previously treated. They must have measurable disease, be in good physical condition (ECOG 0-1), and not have certain genetic mutations (BRAF V600). People can't join if they've had brain metastases, need systemic steroids or immunosuppressants, are allergic to the drugs being tested, or have used checkpoint inhibitors/MEK inhibitors before.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

My cancer's microsatellite status was checked using standard methods.

My colorectal cancer is confirmed to be in stage IV and has been previously treated.

Exclusion Criteria

I have had interstitial lung disease or pneumonitis.

I have an autoimmune disease.

My colorectal cancer has a BRAF V600 mutation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab in combination with trametinib with or without ipilimumab

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Trametinib

Trial Overview The study tests nivolumab combined with trametinib, with some participants also receiving ipilimumab. It aims to see how well these drugs work together in treating colorectal cancer that's spread after previous treatment. Participants will be randomly assigned to different drug combinations.

Participant Groups

Group I: Part 2 Cohort 5 (3L): Regorafenib Experimental Treatment 1 Intervention

Group II: Part 2 Cohort 4 (3L): nivolumab + ipilimumab + trametinib Experimental Treatment 3 Interventions

Group III: Part 1B Cohort 6 (2L): nivolumab + ipilimumab + trametinib Experimental Treatment 3 Interventions

Group IV: Part 1A Cohort 3 (2L): nivolumab + ipilimumab + trametinib Experimental Treatment 3 Interventions

Group V: Part 1A Cohort 2 2nd Line (2L): nivolumab + ipilimumab + trametinib Experimental Treatment 3 Interventions

Group VI: Part 1 Cohort 1 3rd Line (3L): nivolumab + trametinib Experimental Treatment 2 Interventions

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

Bristol-Myers Squibb

Lead Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Findings from Research

In a phase II study involving 45 patients with MSI-H/dMMR metastatic colorectal cancer, the combination of nivolumab and low-dose ipilimumab showed a high objective response rate of 69% and a disease control rate of 84%, indicating strong efficacy as a first-line treatment.

The treatment was well tolerated, with only 22% of patients experiencing grade 3-4 treatment-related adverse events, and 74% of responders maintained their response at the time of data cutoff, suggesting durability of the treatment effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. Lenz, HJ., Van Cutsem, E., Luisa Limon, M., et al.[2022]

Immunotherapy using PD-1 inhibitors shows promising efficacy in treating high-level microsatellite instability (MSI-H) colorectal cancers (CRCs), with a 40% objective response rate in MSI-H patients compared to 0% in microsatellite stable (MSS) patients.

The studies indicate that while PD-1 inhibitors may benefit MSI-H mCRC patients, there is currently no evidence supporting their effectiveness in MSS CRCs, highlighting the need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Potential Value of Immunotherapy in Colorectal Cancers: Review of the Evidence for Programmed Death-1 Inhibitor Therapy. Toh, JWT., de Souza, P., Lim, SH., et al.[2022]

Nivolumab, a PD-1 inhibitor, is approved for treating various cancers, including metastatic colorectal cancer with specific genetic markers (deficient mismatch repair or microsatellite-instability high).

The FDA granted accelerated approval for nivolumab in July 2017 for patients with this type of colorectal cancer who have not responded to standard chemotherapy, highlighting its potential efficacy in a challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer. Mehrvarz Sarshekeh, A., Overman, MJ., Kopetz, S.[2022]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

Nivolumab and ipilimumab, two FDA-approved immunotherapeutic agents targeting PD-1 and CTLA-4, are effective in treating various cancers but can cause significant immune-related adverse effects (irAEs).

In a case study of a 66-year-old female patient, steroid-resistant colitis induced by these checkpoint inhibitors was successfully treated with infliximab, highlighting a potential management strategy for severe irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. Tidwell, C., Gutnik, S.[2020]

A systematic review of 14 randomized controlled trials found that combining nivolumab (NIVO) with ipilimumab (IPI) significantly increases the risk of treatment-related adverse events (TRAEs) compared to NIVO alone, with an overall risk ratio of 1.11 for any grade TRAEs and 1.95 for severe (grade 3 or 4) TRAEs.

Specific adverse events were notably higher with the combination therapy, including colitis (RR = 4.52), pneumonitis (RR = 3.06), and diarrhea (RR = 1.68), indicating that while the combination may be effective, it comes with increased safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis. Kamat, S., Patel, J., Brown, BR., et al.[2022]

Ipilimumab is an immunotherapy that works by inhibiting CTLA-4, leading to enhanced immune system activation, which can effectively treat advanced melanoma and other cancers.

Common side effects of ipilimumab are mostly mild to moderate (grade I or II) and include immune-mediated reactions like inflammatory diarrhea and pruritus, but serious side effects can be managed effectively with corticosteroids or other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab for advanced melanoma: a nursing perspective. Ledezma, B.[2017]

In a pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). [2022]

3. United States pubmed.ncbi.nlm.nih.gov

The Potential Value of Immunotherapy in Colorectal Cancers: Review of the Evidence for Programmed Death-1 Inhibitor Therapy. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Where We Stand With Immunotherapy in Colorectal Cancer: Deficient Mismatch Repair, Proficient Mismatch Repair, and Toxicity Management. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis. [2022]

9. Japan pubmed.ncbi.nlm.nih.gov

Mirroring UC care pathways in refractory immune checkpoint inhibitor (ICI)-mediated colitis: distinct features and common pathways. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Ipilimumab for advanced melanoma: a nursing perspective. [2017]

11. England pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. [2023]